tbuckley/cabot-search huggingface dataset:
Strengthening implementation guidelines for HIV service delivery: Considerations for future evidence generation and synthesis
Authors: Ingrid Eshun-Wilson, Nathan Ford, Aaloke Mody, Laura Beres, Sheree Schwartz, Stefan Baral, Elvin H. Geng
Journal: PLoS Medicine (2023)

With highly effective diagnostic, prevention, and treatment innovations available in HIV programs globally, the HIV field is increasingly turning to implementation and service delivery questions.• Developing guidelines for implementation of interventions is markedly challenged by limitations in primary implementation research design and reporting, as well as difficulties in application of evidence synthesis and guideline development tools originally developed to appraise evidence for efficacy.• Drawing on the processes of developing the WHO HIV service delivery guidelines for testing and treatment between 2018 and 2021, we present challenges and identify areas for future methodological development to improve the incorporation of implementation research across the full spectrum of the evidence generation continuum.• We highlight gaps in design, measurement, and reporting of primary implementation research, as well as underreporting of relevant program data.• We describe how routine application of current evidence synthesis tools may not sufficiently answer implementation questions and propose that methodological tools be optimized to identify high-quality non-randomized evidence and reduce penalization for heterogeneity in meta-analysis of implementation research.• These findings serve as a blueprint for further methodological work to strengthen existing evidence synthesis and guideline development tools for HIV service delivery guidelines and for implementation research more broadly.
Comparison of Reporting Race and Ethnicity in Medical Journals Before and After Implementation of Reporting Guidance, 2019-2022
Authors: Annette Flanagin, Miriam Y. Cintron, Stacy L. Christiansen, Tracy Frey, Timothy Gray, Iris Y. Lo, Roger J. Lewis
Journal: JAMA Network Open (2023)

This cross-sectional study compares race and ethnicity reporting in 3 medical journals before and after implementation of updated guidance on the reporting of race and ethnicity in August 2021.
A Polygenic Risk Score for Prostate Cancer Risk Prediction
Authors: Kerry R. Schaffer, Mingjian Shi, John P. Shelley, Jeffrey J. Tosoian, Linda Kachuri, John S. Witte, Jonathan D. Mosley
Journal: JAMA Internal Medicine (2023)

This retrospective cohort study compares 2 risk calculator systems that compute the probabilities of finding high-grade or any cancer on biopsy results in men undergoing a first prostate biopsy.
Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension
Authors: Marius M Hoeper, David B Badesch, H Ardeschir Ghofrani, J Simon R Gibbs, Mardi Gomberg-Maitland, Vallerie V McLaughlin, Ioana R Preston, Rogerio Souza, Aaron B Waxman, Ekkehard Grünig, Grzegorz Kopeć, Gisela Meyer, Karen M Olsson, Stephan Rosenkranz, Yayun Xu, Barry Miller, Marcie Fowler, John Butler, Joerg Koglin, Janethe de Oliveira Pena, Marc Humbert
Journal: New England Journal of Medicine (2023)

Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension.We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit.A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).
Analysis of risk evaluation and mitigation strategies for teratogenic drugs: Variation in primary and secondary prevention measures
Authors: Beatrice L. Brown, Aaron S. Kesselheim, Ameet Sarpatwari
Journal: PLoS Medicine (2023)

In an analysis of risk evaluation and mitigation strategies for teratogenic drugs, Ameet Sarpatwari, Beatrice Brown and Aaron Kesselheim explore the variation in primary and secondary prevention measures.
Continued Progress in Therapy for Pulmonary Arterial Hypertension
Authors: Darren B. Taichman, Jane A. Leopold, Greg Elliott
Journal: New England Journal of Medicine (2023)

Pulmonary arterial hypertension is a devastating disorder characterized by precapillary pulmonary hypertension not caused by respiratory disease, obstruction of the pulmonary arteries, or certain less-common conditions. Idiopathic pulmonary arterial hypertension, heritable pulmonary arterial hypertension, and pulmonary arterial hypertension associated with a connective-tissue disease or exposure to drugs such as methamphetamine account for most cases in the developed world. For years, pulmonary arterial hypertension was considered to be an untreatable, progressive, and rapidly fatal condition.1 A new era of treatment for patients with pulmonary arterial hypertension began three decades ago. Investigations that were focused on imbalanced vasoconstriction and vasodilation produced groundbreaking . . .
RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels
Authors: Bethan L. Clifford, Kelsey E. Jarrett, Joan Cheng, Angela Cheng, Marcus Seldin, Pauline Morand, Richard Lee, Mary Chen, Angel Baldan, Thomas Q. de Aguiar Vallim, Elizabeth J. Tarling
Journal: Circulation Research (2023)

Background: Removal of circulating plasma low-density lipoprotein cholesterol (LDL-C) by the liver relies on efficient endocytosis and intracellular vesicle trafficking. Increasing the availability of hepatic LDL receptors (LDLRs) remains a major clinical target for reducing LDL-C levels. Here, we describe a novel role for RNF130 (ring finger containing protein 130) in regulating plasma membrane availability of LDLR. Methods: We performed a combination of gain-of-function and loss-of-function experiments to determine the effect of RNF130 on LDL-C and LDLR recycling. We overexpressed RNF130 and a nonfunctional mutant RNF130 in vivo and measured plasma LDL-C and hepatic LDLR protein levels. We performed in vitro ubiquitination assays and immunohistochemical staining to measure levels and cellular distribution of LDLR. We supplement these experiments with 3 separate in vivo models of RNF130 loss-of-function where we disrupted Rnf130 using either ASO (antisense oligonucleotides), germline deletion, or AAV CRISPR (adeno-associated virus clustered regularly interspaced short palindromic repeats) and measured hepatic LDLR and plasma LDL-C. Results: We demonstrate that RNF130 is an E3 ubiquitin ligase that ubiquitinates LDLR resulting in redistribution of the receptor away from the plasma membrane. Overexpression of RNF130 decreases hepatic LDLR and increases plasma LDL-C levels. Further, in vitro ubiquitination assays demonstrate RNF130–dependent regulation of LDLR abundance at the plasma membrane. Finally, in vivo disruption of Rnf130 using ASO, germline deletion, or AAV CRISPR results in increased hepatic LDLR abundance and availability and decreased plasma LDL-C levels. Conclusions: Our studies identify RNF130 as a novel posttranslational regulator of LDL-C levels via modulation of LDLR availability, thus providing important insight into the complex regulation of hepatic LDLR protein levels.
Precision Medicine for Whom? Public Health Outputs from “Genomics England” and “All of Us” to Make Up for Upstream and Downstream Exclusion
Authors: Ilaria Galasso
Journal: The American Journal of Bioethics (2023)

This paper problematizes the precision medicine approach embraced by the All of Us Research Program (US) and by Genomics England (UK) in terms of benefits distribution, by arguing that current "diversity and inclusion" efforts do not prevent exclusiveness, unless the framing and scope of the projects are revisited in public health terms. Grounded on document analysis and fieldwork interviews, this paper analyzes efforts to address potential patterns of exclusion upstream (from participating in precision medicine research) and downstream (from benefitting from precision medicine outputs). It argues that efforts for inclusion upstream are not corresponded downstream, and this unbalance jeopardizes the equitable capacities of the projects. It concludes that enhanced focus on socio-environmental determinants of health and aligned public health interventions as precision medicine outputs would be to the benefit of all and especially of those who are most at risk of (upstream as well as downstream) exclusion.
Microglia–neuron interactions promote chronic itch via the <scp>NLRP3‐IL‐1β‐GRPR</scp> axis
Authors: Xueting Liu, Yanmei Wang, Yueling Zeng, De Wang, Yuhuan Wen, Limin Fan, Ying He, Junyan Zhang, Weimin Sun, Yongping Liu, Ailin Tao
Journal: Allergy (2023)

Spinal astrocytes contribute to chronic itch via sensitization of itch-specific neurons expressing gastrin-releasing peptide receptor (GRPR). However, whether microglia-neuron interactions contribute to itch remains unclear. In this study, we aimed to explore how microglia interact with GRPR+ neurons and promote chronic itch.RNA sequencing, quantitative real-time PCR, western blot, immunohistochemistry, RNAscope ISH, pharmacologic and genetic approaches were performed to examine the roles of spinal NLRP3 (The NOD-like receptor family, pyrin-containing domain 3) inflammasome activation and IL-1β-IL1R1 signaling in chronic itch. Grpr-eGFP and Grpr KO mice were used to investigate microglia-GRPR+ neuron interactions.We observed NLRP3 inflammasome activation and IL-1β production in spinal microglia under chronic itch conditions. Blockade of microglial activation and the NLRP3/caspase-1/IL-1β axis attenuated chronic itch and neuronal activation. Type 1 IL-1 receptor (IL-1R1) was expressed in GRPR+ neurons, which are essential for the development of chronic itch. Our studies also find that IL-1β+ microglia are localized in close proximity to GRPR+ neurons. Consistently, intrathecal injection of IL1R1 antagonist or exogenous IL-1β indicate that the IL-1β-IL-1R1 signaling pathway enhanced the activation of GRPR+ neurons. Furthermore, our results demonstrate that the microglial NLRP3/caspase-1/IL-1β axis contributes to several different chronic itches triggered by small molecules and protein allergens from the environment and drugs.Our findings reveal a previously unknown mechanism in which microglia enhances the activation of GRPR+ neurons through the NLRP3/caspase-1/IL-1β/IL1R1 axis. These results will provide new insights into the pathophysiology of pruritus and novel therapeutic strategies for patients with chronic itch.
Estimation of Multiyear Consequences for Abortion Access in Georgia Under a Law Limiting Abortion to Early Pregnancy
Authors: Sara K. Redd, Elizabeth A. Mosley, Suba Narasimhan, Anna Newton-Levinson, Roula AbiSamra, Carrie Cwiak, Kelli Stidham Hall, Sophie A. Hartwig, Johanna Pringle, Whitney S. Rice
Journal: JAMA Network Open (2023)

Importance Following the US Supreme Court ruling in Dobbs v Jackson Women’s Health Organization , Georgia’s law limiting abortion to early pregnancy, House Bill 481 (HB481), was allowed to go into effect in July 2022. Objectives To estimate anticipated multiyear effects of HB481, which prohibits abortions after detection of embryonic cardiac activity, on abortion incidence in Georgia, and to examine inequities by race, age, and socioeconomic status. Design, Setting, and Participants This repeated cross-sectional analysis used abortion surveillance data from January 1, 2007, to December 31, 2017, to estimate future effects of HB481 on abortion care in Georgia, with a focus on the 2 most recent years of data (2016 and 2017). Abortion surveillance data were obtained from the 2007-2017 Georgia Department of Public Health’s Induced Termination of Pregnancy files. Linear regression was used to estimate trends in abortions provided at less than 6 weeks’ gestation and at 6 weeks’ gestation or later in Georgia, and χ 2 analyses were used to compare group differences by race, age, and educational attainment. Data were analyzed from July 26 to September 22, 2022. Exposures HB481, Georgia’s law limiting abortion to early pregnancy. Main Outcome and Measures Weeks’ gestation at abortion (&amp;amp;lt;6 vs ≥6 weeks). Results From January 1, 2007, to December 31, 2017, there were 360 972 reported abortions in Georgia, with an annual mean (SD) of 32 816 (1812) abortions. Estimates from 2016 to 2017 suggest that 3854 abortions in Georgia (11.6%) would likely meet eligibility requirements for abortion care under HB481. Fewer abortions obtained by Black patients (1943 [9.6%] vs 1280 [16.2%] for White patients), patients younger than 20 years (261 [9.1%] vs 168 [15.0%] for those 40 years and older), and patients with fewer years of education (392 [9.2%] with less than a high school diploma and 1065 [9.6%] with a high school diploma vs 2395 [13.5%] for those with some college) would likely meet eligibility requirements under HB481. Conclusions and Relevance These findings suggest that Georgia’s law limiting abortion to early pregnancy (HB481) would eliminate access to abortion for nearly 90% of patients in Georgia, and disproportionately harm patients who are Black, younger, and in lower socioeconomic status groups.
Nucleophosmin plays a role in repairing DNA damage and is a target for cancer treatment
Authors: Konjeti R. Sekhar, Michael L. Freeman
Journal: Cancer Research (2023)

Abstract Nucleophosmin (NPM1) is frequently mutated in acute myeloid leukemia, and NPM1 expression is elevated in several cancer types. NPM1 is a multifunctional oligomeric protein involved in numerous cellular functions that include participating in liquid–liquid phase separation, ribosome biogenesis, chaperoning of histones, and modulation of transcription. In this review, we discuss the underappreciated role of NPM1 in DNA damage repair, specifically Polη-mediated translesion synthesis, base excision, and homologous recombination and highlight the therapeutic potential of NPM1 targeting in cancer treatment.
Importance of Designing Trials for Older Adults With Complex Medical Conditions
Authors: Andrew J. Foy, David L. Brown
Journal: JAMA Internal Medicine (2023)

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Doxorubicin and erastin co-loaded hydroxyethyl starch-polycaprolactone nanoparticles for synergistic cancer therapy
Authors: Chen Xu, Shiyou Li, Jitang Chen, Huimin Wang, Zheng Li, Qingyuan Deng, Jiayuan Li, Xing Wang, Yuxuan Xiong, Zhijie Zhang, Xiangliang Yang, Zifu Li
Journal: Journal of Controlled Release (2023)
Individualized Treatment Effects of Bougie versus Stylet for Tracheal Intubation in Critical Illness
Authors: Kevin P. Seitz, Alexandra B. Spicer, Jonathan D. Casey, Kevin G. Buell, Edward T. Qian, Emma J. Graham Linck, Brian E. Driver, Wesley H. Self, Adit A. Ginde, Stacy A. Trent, Sheetal Gandotra, Lane M. Smith, David B. Page, Derek J. Vonderhaar, Jason R. West, Aaron M. Joffe, Kevin C. Doerschug, Christopher G. Hughes, Micah R. Whitson, Matthew E. Prekker, Todd W. Rice, Pratik Sinha, Matthew W. Semler, Matthew M. Churpek
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: A recent randomized trial found that using a bougie did not increase the incidence of successful intubation on first attempt in critically ill adults. The average effect of treatment in a trial population, however, may differ from effects for individuals. Objective: We hypothesized that application of a machine learning model to data from a clinical trial could estimate the effect of treatment (bougie vs stylet) for individual patients based on their baseline characteristics (“individualized treatment effects”). Methods: Secondary analysis of the Bougie or Stylet in Patients Undergoing Intubation Emergently (BOUGIE) trial. A causal forest algorithm was used to model differences in outcome probabilities by randomized group assignment (bougie vs stylet) for each patient in the first half of the trial (training cohort). This model was used to predict individualized treatment effects for each patient in the second half (validation cohort). Measurements and Main Results: Of 1,102 patients in BOUGIE, 558 (50.6%) were the training cohort, and 544 (49.4%) were the validation cohort. In the validation cohort, individualized treatment effects predicted by the model significantly modified the effect of trial group assignment on the primary outcome (P-value for interaction =0.02; adjusted qini coefficient, 2.46). The most important model variables were difficult airway characteristics, body mass index, and APACHE II score. Conclusions: In this hypothesis-generating secondary analysis of a randomized trial with no average treatment effect and no treatment effect in any prespecified subgroups, a causal forest machine learning algorithm identified patients who appeared to benefit from use of a bougie over a stylet and from use of a stylet over a bougie using complex interactions between baseline patient and operator characteristics.
Assessment of a Peer Physician Coaching Partnership Between a Designated Cancer Center Genetics Service and a Community Cancer Network Hospital
Authors: Lauren G. Santos, Tatyana Buzdnitskaya, Bradley A. Rolf, William Souza, Mark Sienko, Jose Alberto Ruiz-Bonilla, Binay Shah, Patrick Jewell, Lindsay Jensen, Martha Horike-Pyne, Jo Ann Elrod, Jennie Crews, Mercy Laurino, Kevin Austin Weeks, Marianne E. Dubard-Gault
Journal: JAMA Network Open (2023)

Background Patients with cancer seen in rural and underserved areas disproportionately face barriers to access genetic services. Genetic testing is critical to inform treatment decisions, for early detection of another cancer, and to identify at-risk family members who may benefit from screening and prevention. Objective To examine medical oncologists’ genetic testing ordering trends for patients with cancer. Design, Setting, and Participants This prospective quality improvement study was performed in 2 phases over 6 months between August 1, 2020, and January 31, 2021, at a community network hospital. Phase 1 focused on observation of clinic processes. Phase 2 incorporated peer coaching from cancer genetics experts for medical oncologists at the community network hospital. The follow-up period lasted 9 months. Main Outcomes and Measures The number of genetic tests ordered was compared between phases. Results The study included 634 patients (mean [SD] age, 71.0 [10.8] years [range, 39-90 years]; 409 women [64.5%]; 585 White [92.3%]); 353 (55.7%) had breast cancer, 184 (29.0%) had prostate cancer, and 218 (34.4%) had a family history of cancer. Of the 634 patients with cancer, 29 of 415 (7.0%) received genetic testing in phase 1, and 25 of 219 (11.4%) received genetic testing in phase 2. Of the 29 patients who received testing in phase 1, 20 (69.0%) had germline genetic testing; 23 of 25 patients (92.0%) had germline genetic testing in phase 2. Uptake of germline genetic testing increased by 23.0% between phases, but the difference was not statistically significant ( P = .06). Uptake of germline genetic testing was highest among patients with pancreatic cancer (4 of 19 [21.1%]) and ovarian cancer (6 of 35 [17.1%]); the National Comprehensive Cancer Network (NCCN) recommends offering genetic testing to all patients with pancreatic cancer and ovarian cancer. Conclusions and Relevance This study suggests that peer coaching from cancer genetics experts was associated with an increase in ordering of genetic testing by medical oncologists. Efforts made to (1) standardize gathering of personal and family history of cancer, (2) review biomarker data suggestive of a hereditary cancer syndrome, (3) facilitate ordering tumor and/or germline genetic testing every time NCCN criteria are met, (4) encourage data sharing between institutions, and (5) advocate for universal coverage for genetic testing may help realize the benefits associated with precision oncology for patients and their families seeking care at community cancer centers.